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COUP-TFI regulates the balance of cortical patterning between frontal/motor and sensory areas

Abstract

We used cortex-specific deletion of the transcription factor gene COUP-TFI (also known as Nr2f1) in mice to demonstrate previously unknown fundamental roles for it in patterning mammalian neocortex into areas. The highest COUP-TFI expression is observed in the cortical progenitors and progeny in parietal and occipital cortex that form sensory areas, and the lowest expression was observed in frontal cortex that includes motor areas. Cortical deletion of COUP-TFI resulted in massive expansion of frontal areas, including motor, to occupy most of neocortex, paralleled by marked compression of sensory areas to caudal occipital cortex. These area patterning changes are preceded and paralleled by corresponding changes in molecular markers of area identity and altered axonal projections to maintain patterned area-specific input and output connections. We conclude that COUP-TFI is required for balancing patterning of neocortex into frontal/motor and sensory areas by acting in its expression domain to repress frontal/motor area identities and to specify sensory area identities.

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Figure 1: Cortex-specific inactivation of COUP-TFI in COUP-TFIfl/flEmx1Cre mice.
Figure 2: Primary sensory areas are substantially reduced in size and compressed ectopically to caudal occipital cortex in COUP-TFIfl/flEmx1Cre mice.
Figure 3: COUP-TFIfl/flEmx1Cre mice show area- and layer-specific molecular and cytoarchitectural characteristics that parallel changes in area patterning.
Figure 4: Correct topography between thalamus and cortex to reduced, ectopic sensory areas is maintained in COUP-TFIfl/flEmx1Cre mice.
Figure 5: Expansion of the frontal area and reduction of somatosensory and visual areas in COUP-TFIfl/flEmx1Cre mice.
Figure 6: Altered expression of regionalized markers in COUP-TFI fl/flEmx1-Cre embryos.
Figure 7: Changes in region-specific connections between the cortex and thalamus in COUP-TFIfl/flEmx1Cre mice.
Figure 8: Somatosensory neurons behave like motor neurons in COUP-TFIfl/flEmx1Cremice.

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Acknowledgements

We would like to thank A. Simeone for Emx2, P. Gruss for Pax6, I. Mason for Fgf8, M. Takeichi for Cdh8, M. Tsai for COUP-TFI, M. Israel for Id2, P. Arlotta for Fezf2, P. Vanderhaeghen for Efna5 riboprobes, R. Hevner for the Tbr1 antibody, M. Tsai for the COUP-TFI genomic fragments, K. Jones for the Emx1-IRES-Cre line, the TIGEM Transgenic and Knockout Core facility for helping to generate the COUP-TFIfloxed line, G. Andolfi for genotyping, M. Giordano for animal husbandry, and our respective lab personnel for fruitful discussions. M.S. would like to thank H. Teichmann for the Tbr1 P8 sagittal sections, and J.L.R. Rubenstein and A. Faedo for sharing data and fruitful discussion. D.D.M.O. and S.-J.C. thank T. Hamasaki for teaching S.-J.C. the methods of flattened tangential sections and whole mount in situ hybridization, and B. Higgins for re-deriving, maintaining and genotyping the conditional COUP-TFI line obtained from M. Studer. This work was supported by the Italian Telethon Foundation and by the European Community FP6 program under grant number LSHM-CT-2004-005139 (M.S.), and US National Institute of Neural Disorders and Stroke grants R37 NS31558 and R01 NS50646 (D.D.M.O.).

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Contributions

M.A. generated the COUP-TIfloxed mice and carried out tracing experiments at embryonic stages. S.-J.C. carried out in situ hybridization and histo- and immunostaining experiments at postnatal ages. G.S.T. performed in situ hybridization and immunostaining experiments at embryonic stages. A.L. and S.-J.C. performed tracing experiments at P7. M.A., S.-J.C., G.S.T., A.L., D.D.M.O. and M.S. designed the experiments and analyzed the data, and D.D.M.O. and M.S. wrote the paper.

Corresponding authors

Correspondence to Dennis D M O'Leary or Michèle Studer.

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Armentano, M., Chou, SJ., Srubek Tomassy, G. et al. COUP-TFI regulates the balance of cortical patterning between frontal/motor and sensory areas. Nat Neurosci 10, 1277–1286 (2007). https://doi.org/10.1038/nn1958

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